This invention relates to a new process for the preparation of novel substituted haloarene compounds that comprises a novel and efficient selective mono-lithiation of a dihaloarene by an organo-lithium compound in the presence of an enolizable carbonyl reactant. In the process of the instant invention the newly formed lithiated haloarene is immediately quenched in situ by the carbonyl reactant to form said substituted haloarene. The process of the instant invention operates at higher temperatures and higher concentrations and is more efficient than conventional methods in which the aryl lithium species is first formed and the carbonyl reactant is added in a subsequent step. High yields of the substituted haloarene are obtained in a practical one-step process since competitive addition of the organo-lithium compound to the carbonyl reactant and di-substitution of the arene occur only to a minor extent.
H.-G. Schmalz (CPC-User Forum, Frankfurt/Main, Germany, Dec. 3, 2003; Cambridge Healthtech Institute, Eleventh Annual Advancing Library Design and Organic Synthesis, La Jolla, Calif., Feb. 25, 2004) has described an in situ quench (ISQ) protocol wherein n-butyllithium is added to a preformed mixture of bromoarene and ketone under both batch and flow conditions. This protocol requires sterically hindered, non-enolizable ketones or the use of tertiary-butyllithium and cryogenic temperatures (−78° C.) for enolizable substrates.
US Published Application No. 20020016470A1; and X. Wang, et al., Tetrahedron Lett., 41:4335 (2000), describe reactions of 2,5-dibromopyridine with n-butyllithium which selectively lithiate in the 2-position if the solvent is toluene and in the 5-position if the solvent is tetrahydrofuran. The lithiation and quench are carried out sequentially at temperatures of −50° C. to −78° C. The concentration of the substrate in solution is 0.085M–0.28M, although at 0.28M the reagents and products are not entirely soluble.
W. Li, et al. J. Org. Chem., 67:5394(2002), describe an n-butyllithium in situ quench protocol for the preparation of arylboronic acids from the reaction of substrates such as 3-bromopyridine with borates (borates are non-enolizable).
F. D. Therkelsen, et al., Org. Lett., 6:1991(2004), details Barbier-type protocols (in situ quench) for the metallation of 4-halopyrimidines and in situ quench with electrophiles such as aldehydes. The metallation agents used were either magnesium ate complexes or butyllithium. The magnesium “ate” complexes worked effectively at both low (−76° C.) temperatures and 0° C. However, with n-butyllithium, the reaction only worked at −76° C. and no desired product was observed at 0° C. Additionally, with either metallation reagent, the in situ quench (Barbier) conditions did not work with a ketone as the electrophile.
PCT International Publication WO01/90072A1 describes the metallation of halo-heteroarylamine compounds using organomagnesium (Grignard) reagents. There, the lithiation of 2,5-dibromopyridine under cryogenic and high dilution conditions with the selectivity dependent on reaction time is taught to not be suitable for large scale synthesis.
The present invention describes an in situ quench protocol wherein n-butyllithium is added to a preformed mixture of a dihaloarene and ketone, including enolizable ketones, under both batch and flow conditions to selectively form a mono-substituted haloarene at non-cryogenic temperatures and relatively high concentrations of substrate.
The substituted haloarenes produced by the process of the present invention are useful intermediates in the preparation of N-aryl or N-heteroaryl substituted pharmaceutically active compounds that include selective antagonists, inverse agonists and partial agonists of serotonin 1 (5-HT1) receptors useful in treating or preventing depression, anxiety, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT1 agonist or antagonist is indicated.